多巴胺受体的cDNA克隆

通过多巴胺受体的5个cDNA克隆,综述和分析了5个多巴胺受体(D₁R-D₅R)的基因结构,在染色体上的定位及其mRNA在中枢脑区的分布;比较了这5个受体cDNA克隆的结构特征和药理学性质.     

Potentiation of temozolomide antitumor effect by purine receptor ligands able to restrain the in vitro growth of human glioblastoma stem cells

Glioblastoma multiforme (GBM), the most common and aggressive brain tumor in humans, comprises a population of stem-like cells (GSCs) that are currently investigated as potential target for GBM therapy. Here, we used GSCs isolated from three different GBM surgical specimens to examine the antitumor activity of purines. Cultured GSCs expressed either metabotropic adenosine P1 and ATP P2Y receptors or ionotropic P2X₇ receptors. GSC exposure for 48 h to 10–150 μM ATP, P2R ligand, or to ADPβS or MRS2365, P2Y₁R agonists, enhanced cell expansion. This effect was counteracted by the PY₁R antagonist MRS2500. In contrast, 48-h treatment with higher doses of ATP or UTP, which binds to P2Y_2/4R, or 2′(3′)-O-(4-benzoylbenzoyl)-ATP (Bz-ATP), P2X₇R agonist, decreased GSC proliferation. Such a reduction was due to apoptotic or necrotic cell death but mostly to growth arrest. Accordingly, cell regrowth and secondary neurosphere formation were observed 2 weeks after the end of treatment. Suramin, nonselective P2R antagonist, MRS1220 or AZ11645373, selective A₃R or P2X₇R antagonists, respectively, counteracted ATP antiproliferative effects. AZ11645373 also abolished the inhibitory effect of Bz-ATP low doses on GSC growth. These findings provide important clues on the anticancer potential of ligands for A₃R, P2Y₁R, and P2X₇R, which are involved in the GSC growth control. Interestingly, ATP and BzATP potentiated the cytotoxicity of temozolomide (TMZ), currently used for GBM therapy, enabling it to cause a greater and long-lasting inhibitory effect on GSC duplication when readded to cells previously treated with purine nucleotides plus TMZ. These are the first findings identifying purine nucleotides as able to enhance TMZ antitumor efficacy and might have an immediate translational impact.     

New dual ligands for the D2 and 5-HT1A receptors from the group of 1,8-naphthyl derivatives of LCAP

More than 300 million people are suffering from depression, one of the civilization diseases in the 21st century. Serotonin 5-HT_1AR and dopamine D₂R play an important role in the treatment and pathogenesis of depression. Moreover, in recent years, the efficacy of dual 5-HT_1A/D₂ receptors ligands has been demonstrated in the fight against depression. In this work the new bulky arylpiperazine derivatives (LCAP) were synthesized in microwave radiation field. The affinities for the selected serotonin (5-HT_1A,5-HT_2A,5-HT₆,5-HT₇) and dopamine (D₂) receptors have been evaluated in vitro. Compounds 5.3a, 5.4, 5.1c, 5.3d, 5.2a are promising dual 5-HT_1AR/D₂R ligands. The SAR analysis were additionally supported with molecular docking studies.     

Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation

Serotonin (5-hydroxytryptamine, 5-HT) is, without doubt, the neurotransmitter for which the number of receptors is the highest. Fifteen genes encoding functional 5-HT receptors have been cloned in mammalian brain. 5-HT₃ receptors are ionotropic receptors, whereas all the others are metabotropic G-protein-coupled receptors (GPCRs). 5-HT receptor diversity is further increased by post-genomic modifications, such as alternative splicing (up to 10 splice variants for the 5-HT₄ receptor) or by mRNA editing in the case of 5-HT_2C receptors. The cellular and behavioral implications of 5-HT_2C receptor editing are of great physiological importance. Signaling of 5-HT receptors involves a great variety of pathways, but only some of these have been demonstrated in neurons. The classical view of neurotransmitter receptors localized within the synaptic cleft cannot be applied to 5-HT receptors, which are mostly (but not exclusively) localized at extra-synaptic locations either pre- or post-synaptically. 5-HT receptors are engaged in pre- or post-synaptic complexes composed of many GPCR-interacting proteins. The functions of these proteins are starting to be revealed. These proteins have been implicated in targeting, trafficking to or from the membrane, desensitization, and fine-tuning of signaling.     

Design and synthesis of novel N-sulfonyl-2-indoles that behave as 5-HT6 receptor ligands with significant selectivity for D3 over D2 receptors

All clinically-used antipsychotics display similar affinity for both D₂ (D2R) and D₃ (D3R) receptors, and they likewise act as 5-HT_2A receptor antagonists. They provide therapeutic benefit for positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive or negative symptoms. Since blockade of D₃ and 5-HT₆ (5-HT6R) receptors enhances neurocognition and social cognition, and potentially improves negative symptoms, a promising approach for improved treatment for schizophrenia would be to develop drugs that preferentially act at D3R versus D2R and likewise recognize 5-HT6R. Starting from the high affinity 5-HT6R ligands I and II, we identified compounds 11a and 14b that behave as 5-HT6R ligands with significant selectivity for D3R over D2R.     

Stabilization of the GluCl Ligand-Gated Ion Channel in the Presence and Absence of Ivermectin

Improving our understanding of the mechanisms and effects of anesthetics is a critically important part of neuroscience. The currently dominant theory is that anesthetics and similar molecules act by binding to Cys-loop receptors in the postsynaptic terminal of nerve cells and potentiate or inhibit their function. Although structures for some of the most important mammalian channels have still not been determined, a number of important results have been derived from work on homologous cationic channels in bacteria. However, partly due to the lack of a nervous system in bacteria, there are a number of questions about how these results relate to higher organisms. The recent determination of a structure of the eukaryotic chloride channel, GluCl, is an important step toward accurate modeling of mammalian channels, because it is more similar in function to human Cys-loop receptors such as GABA_AR or GlyR. One potential issue with using GluCl to model other receptors is the presence of the large ligand ivermectin (IVM) positioned between all five subunits. Here, we have performed a series of microsecond molecular simulations to study how the dynamics and structure of GluCl change in the presence versus absence of IVM. When the ligand is removed, subunits move at least 2 Å closer to each other compared to simulations with IVM bound. In addition, the pore radius shrinks to 1.2 Å, all of which appears to support a model where IVM binding between subunits stabilizes an open state, and that the relaxed nonIVM conformations might be suitable for modeling other channels. Interestingly, the presence of IVM also has an effect on the structure of the important loop C located at the neurotransmitter-binding pocket, which might help shed light on its partial agonist behavior.     

Probing residues in the pore-forming (M2) domain of the Cys-loop receptor homologue GLIC reveals some unusual features

Abstract

Cys-loop receptors play important roles in signal transduction. The Gloeobacter ligand-gated ion channel (GLIC) pore binds similar compounds to Cys-loop receptor pores, but has the advantage of known structures in open and closed states. GLIC is activated by protons with a pEC₅₀ of 5.4, and has a histidine residue (His 11’) in its pore-forming α-helix (M2) which is involved in gating. Here we explore the role of this His and other M2 residues using two-electrode voltage clamp of mutant receptors expressed in oocytes. We show that 11’His is very sensitive to substitution; replacement with a range of amino acids ablates function. Similarly altering its location in M2 to the 8’, 9’, 10’, 12’, 13’ or 14’ positions ablated function. Most substitutions of Ser6’ or Ile9’ were also non-functional, although not Ile9’Leu and Ile9’Val. Unexpectedly, an Ile9’His substitution was constitutively active at pH 7, but closed as [H+] increased, with a pIC₅₀ of 5.8. Substitution at 2’, 5’ and 7’ had little effect on pEC₅₀. Overall the data show Ser6’ and His11’ are critical for the function of the receptor, and thus distinguish the roles of these M2 residues from those of Cys-loop receptors, where substitutions are mostly well tolerated. These data suggest modellers should be aware of these atypical features when using the GLIC pore as a model for Cys-loop receptor pores.     

Mutagenic Analysis of the Intracellular Portals of the Human 5-HT3A Receptor

Structural models of Cys-loop receptors based on homology with the Torpedo marmorata nicotinic acetylcholine receptor infer the existence of cytoplasmic portals within the conduction pathway framed by helical amphipathic regions (termed membrane-associated (MA) helices) of adjacent intracellular M3-M4 loops. Consistent with these models, two arginine residues (Arg⁴³⁶ and Arg⁴⁴⁰) within the MA helix of 5-hydroxytryptamine type 3A (5-HT₃A) receptors act singularly as rate-limiting determinants of single-channel conductance (γ). However, there is little conservation in primary amino acid sequences across the cytoplasmic loops of Cys-loop receptors, limiting confidence in the fidelity of this particular aspect of the 5-HT₃A receptor model. We probed the majority of residues within the MA helix of the human 5-HT₃A subunit using alanine- and arginine-scanning mutagenesis and the substituted cysteine accessibility method to determine their relative influences upon γ. Numerous residues, prominently those at the 435, 436, 439, and 440 positions, were found to markedly influence γ. This approach yielded a functional map of the 5-HT₃A receptor portals, which agrees well with the homology model.     

Cardioprotective effects of adenosine A1 and A 3 receptor activation during hypoxia in isolated rat cardiac myocytes

Adenosine (ADO) is a well-known regulator of a variety of physiological functions in the heart. In stress conditions, like hypoxia or ischemia, the concentration of adenosine in the extracellular fluid rises dramatically, mainly through the breakdown of ATP. The degradation of adenosine in the ischemic myocytes induced damage in these cells, but it may simultaneously exert protective effects in the heart by activation of the adenosine receptors. The contribution of ADO to stimulation of protective effects was reported in human and animal hearts, but not in rat hearts. The aim of this study was to evaluate the role of adenosine A₁ and A₃ receptors (A₁R and A₃R), in protection of isolated cardiac myocytes of newborn rats from ischemic injury. The hypoxic conditions were simulated by exposure of cultured rat cardiomyocytes (4–5 days in vitro), to an atmosphere of a N₂ (95%) and CO₂ (5%) mixture, in glucose-free medium for 90 min. The cardiotoxic and cardioprotective effects of ADO ligands were measured by the release of lactate dehydrogenase (LDH) into the medium. Morphological investigation includes immunohistochemistry, image analysis of living and fixed cells and electron microscopy were executed. Pretreatment with the adenosine deaminase considerably increased the hypoxic damage in the cardiomyocytes indicating the importance of extracellular adenosine. Blocking adenosine receptors with selective A₁ and A₃ receptor antagonists abolished the protective effects of adenosine. A₁R and A₃R activation during the hypoxic insult delays onset of irreversible cell injury and collapse of mitochondrial membrane potential as assessed using DASPMI fluorochrom. Cardioprotection induced by the A₁R agonist, CCPA, was abolished by an A₁R antagonist, DPCPX, and was not affected by an A₃R antagonist, MRS1523. Cardioprotection caused by the A₃R agonist, Cl-IB-MECA, was antagonized completely by MRS1523 and only partially by DPCPX. Activation of both A₁R and A₃R together was more efficient in protection against hypoxia than by each one alone. Our study indicates that activation of either A₁ or A₃ adenosine receptors in the rat can attenuate myocyte injury during hypoxia. Highly selective A₁R and A₃R agonists may have potential as cardioprotective agents against ischemia or heart surgery.     

On the role of histamine receptors in regulating pigmentary responses in Oreochromis mossambicus melanophores

Purpose: The present work was carried out to reveal the involvement of histamine receptors at the neuro-melanophore junction of teleost, Oreochromis mossambicus.

Methods: The isolated scale melanophores were assayed using the mean melanophore size index and their responses were recorded in presence of various concentrations of histamine along with H₁ and H₂ receptor specific agonists and antagonist and potentiator compound 48/80.

Results: Melanophores showed high sensitivity to histamine and its specific agonists. Histamine caused a dose-dependent pigment aggregation, whereas 2-(2-Pyridyl) ethylamine (PEA), a specific H₁R agonist also caused aggregation in a similar manner. Conversely, amthamine, a specific H₂R agonist resulted in pigment dispersion. The effects were antagonized by mepyramine; specific H₁R antagonist and ranitidine a specific H₂R antagonist.

Conclusion: It is concluded that O. mossambicus melanophores have both H₁ and H₂ receptors which mediate melanophore aggregation and dispersion respectively. Compound 48/80 augmented the melanin-aggregating and dispersing effects of PEA and amthamine. It is suggested that the effect of histamine is directly mediated through H1 and H2 receptors, whereas H1Rs may be predominantly involved in the aggregatory responses.     

Presence of insulinlike growth factor receptors and lack of insulin receptors on fetal bovine smooth muscle cells

Summary Previous investigations have demonstrated specific receptors and associated mitogenic actions for insulin and insulinlike growth factors I and II (IGF-I and II) in postnatal bovine aortic smooth muscle. Using fetal tissue we have observed different patterns of binding and action for these peptides. Smooth muscle cells isolated from near-term fetal bovine aortae were studied in early passage. Specific receptors for both IGF-I and IGF-II were identified. Specific binding averaged 5.7%/2.5×10⁵ cells for IGF-I, and 16.2% for IGF-II, and 0.3% for insulin. High affinity K _d for both IGF receptors were nanomolar. IGF-II was fivefold less potent than IGF-I in displacing IGF-I binding. IGF-I showed no affinity for the IGF-II receptor. Insulin, at physiologic concentrations, was incapable of displacing either IGF-I or IGF-II binding. Cellular incorporation of [methyl-³H]thymidine was stimulated at the lowest dose of IGF-I tested, 0.5 ng/ml. IGF-II showed no effect up to 100 ng/ml, after which a sharp increase in incorporation was noted. Insulin had a similar effect only at concentrations >0.5 μg/ml, with a maximal response noted at 5 to 10 μg/ml. Our results indicate that fetal bovine aortic smooth muscle cells have an abundance of IGF receptors but lack specific insulin receptors. In addition, IGF-II binding levels are three times higher than for IGF-I. These results are consistent with observations in other species, in which a predominance of IGF over insulin receptors has been demonstrated in fetal tissue, and provide further evidence for a role for the IGFs in embryonic cellular metabolism. This project was supported by grants AM22190 (R. L. H.), AM28229 (R. G. R.) from the National Institutes of Health, Bethesda, MD, and Research Career Development Award AM01275 from the NIH (R. G. R.). Dr. Lee was the recipient of a fellowship award from the Juvenile Diabetes Foundation International and is currently supported by funds from the American Diabetes Association. Dr. Benitz is the recipient of a Clinician-Scientist Award from the American Heart Association, with funds contributed in part by the California Affiliate.     

Subcellular vesicular aggregations of GABA<Subscript>B</Subscript> R1a and R1b receptors increase with age in neurons of the developing mouse brain

GABA_B receptors play a critical neuromodulatory role in the central nervous system. It has been suggested that both the functional role and the cellular distribution of GABA_B receptors in the neuronal network change during post-natal maturation. In the present study, the cellular and subcellular distribution patterns of the GABA_B R1a/b receptors have been analysed in different brain regions of the mouse using immunocytochemistry with isoform-specific antisera. GABA_B R1-immunoreactivity (IR) was present from the first post-natal day (P0) on in most regions of the brain. Neurones exhibited diffuse GABA_B R1-IR labelling throughout somata and larger proximal dendrites as well as some fine neuronal processes. After P5, distinct punctuated staining was apparent. The number of such GABA_B IR granules per cell increased with age in a sigmoidal manner from P5 to P60. Electron microscopy revealed GABA_B IR as clusters of small clear vesicles of 30–50 nm diameter within the cytoplasm and close to the cell membrane at extrasynaptic locations, as well as at pre-synaptic and post-synaptic specialisations. The increase in GABA_B R1-IR punctuate staining during brain maturation points to increasing functional participation and heterogeneity of GABA_B receptors as the complexity of the central nervous system expands with growth and development.The first three authors contributed equally to the study. S.W.S. and W.Z. are co-senior authors.This project was supported by the Deutsche Forschungsgemeinschaft (CMPB to WZ).     

Stabilization of the GluCl Ligand-Gated Ion Channel in the Presence and?Absence of Ivermectin

Improving our understanding of the mechanisms and effects of anesthetics is a critically important part of neuroscience. The currently dominant theory is that anesthetics and similar molecules act by binding to Cys-loop receptors in the postsynaptic terminal of nerve cells and potentiate or inhibit their function. Although structures for some of the most important mammalian channels have still not been determined, a number of important results have been derived from work on homologous cationic channels in bacteria. However, partly due to the lack of a nervous system in bacteria, there are a number of questions about how these results relate to higher organisms. The recent determination of a structure of the eukaryotic chloride channel, GluCl, is an important step toward accurate modeling of mammalian channels, because it is more similar in function to human Cys-loop receptors such as GABA_AR or GlyR. One potential issue with using GluCl to model other receptors is the presence of the large ligand ivermectin (IVM) positioned between all five subunits. Here, we have performed a series of microsecond molecular simulations to study how the dynamics and structure of GluCl change in the presence versus absence of IVM. When the ligand is removed, subunits move at least 2 Å closer to each other compared to simulations with IVM bound. In addition, the pore radius shrinks to 1.2 Å, all of which appears to support a model where IVM binding between subunits stabilizes an open state, and that the relaxed nonIVM conformations might be suitable for modeling other channels. Interestingly, the presence of IVM also has an effect on the structure of the important loop C located at the neurotransmitter-binding pocket, which might help shed light on its partial agonist behavior.     

Human neutrophils do not express purinergic P2X7 receptors

It has been reported that in human neutrophils, external ATP activates plasma membrane purinergic P2X₇ receptors (P2X₇R) to elicit Ca²⁺ entry, production of reactive oxygen species (ROS), processing and release of pro-inflammatory cytokines, shedding of adhesion molecules and uptake of large molecules. However, the expression of P2X₇R at the plasma membrane of neutrophils has also been questioned since these putative responses are not always reproduced. In this work, we used electrophysiological recordings to measure functional responses associated with the activation of membrane receptors, spectrofluorometric measurements of ROS production and ethidium bromide uptake to asses coupling of P2X₇R activation to downstream effectors, immune-labelling of P2X₇R using a fluorescein isothiocyanate-conjugated antibody to detect the receptors at the plasma membrane, RT-PCR to determine mRNA expression of P2X₇R and Western blot to determine protein expression in neutrophils and HL-60 cells. None of these assays reported the presence of P2X₇R in the plasma membrane of neutrophils and non-differentiated or differentiated HL-60 cells—a model cell for human neutrophils. We concluded that P2X₇R are not present at plasma membrane of human neutrophils and that the putative physiological responses triggered by external ATP should be reconsidered.     

Discovery of a novel allosteric modulator of 5-HT3 receptors: inhibition and potentiation of Cys-loop receptor signaling through a conserved transmembrane intersubunit site

The ligand-gated ion channels in the Cys-loop receptor superfamily mediate the effects of neurotransmitters acetylcholine, serotonin, GABA, and glycine. Cys-loop receptor signaling is susceptible to modulation by ligands acting through numerous allosteric sites. Here we report the discovery of a novel class of negative allosteric modulators of the 5-HT(3) receptors (5-HT(3)Rs). PU02 (6-[(1-naphthylmethyl)thio]-9H-purine) is a potent and selective antagonist displaying IC(50) values of ~1 μM at 5-HT(3)Rs and substantially lower activities at other Cys-loop receptors. In an elaborate mutagenesis study of the 5-HT(3)A receptor guided by a homology model, PU02 is demonstrated to act through a transmembrane intersubunit site situated in the upper three helical turns of TM2 and TM3 in the (+)-subunit and TM1 and TM2 in the (-)-subunit. The Ser(248), Leu(288), Ile(290), Thr(294), and Gly(306) residues are identified as important molecular determinants of PU02 activity with minor contributions from Ser(292) and Val(310), and we propose that the naphthalene group of PU02 docks into the hydrophobic cavity formed by these. Interestingly, specific mutations of Ser(248), Thr(294), and Gly(306) convert PU02 into a complex modulator, potentiating and inhibiting 5-HT-evoked signaling through these mutants at low and high concentrations, respectively. The PU02 binding site in the 5-HT(3)R corresponds to allosteric sites in anionic Cys-loop receptors, which emphasizes the uniform nature of the molecular events underlying signaling through the receptors. Moreover, the dramatic changes in the functional properties of PU02 induced by subtle changes in its binding site bear witness to the delicate structural discrimination between allosteric inhibition and potentiation of Cys-loop receptors.     

Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels

Background  

Acetylcholine receptor type ligand-gated ion channels (ART-LGIC; also known as Cys-loop receptors) are a superfamily of proteins that include the receptors for major neurotransmitters such as acetylcholine, serotonin, glycine, GABA, glutamate and histamine, and for Zn²⁺ ions. They play a central role in fast synaptic signaling in animal nervous systems and so far have not been found outside of the Metazoa.     

Chronic Effects of Xanthines on Levels of Central Receptors in Mice

1.Chronic ingestion of caffeine causes a significant increase in levels of A₁-adenosine, nicotinic and muscarinic receptors, serotonergic receptors, GABA_A receptors and L-type calcium channels in cerebral cortical membranes from mice NIH Swiss strain mice.2.Chronic theophylline and paraxanthine had effects similar to those of caffeine except that levels of L-type channels were unchanged. Chronic theobromine, a weak adenosine antagonist, and 1-isobutyl-3-methylxanthine (IBMX), a potent adenosine antagonist and phosphodiesterase inhibitor, caused only an increase in levels of A₁-adenosine receptors. A combination of chronic caffeine and IBMX had the same effects on receptors as caffeine alone. Chronic 3,7-dimethyl-1-propargylxanthine (DMPX), a somewhat selective A_2A-antagonist, caused only an increase in levels of A₁-adenosine receptors. Pentoxyfylline, an adenosine-uptake inhibitor inactive at adenosine receptors, had no effect on receptor levels or calcium channels.3.A comparison of plasma and brain levels of xanthines indicated that caffeine penetrated more readily and attained somewhat higher brain levels than theophylline or theobromine. Penetration and levels were even lower for IBMX, paraxanthine, DMPX, and pentoxyfylline.4.The results suggest that effective blockade of both A₁ and A_2A-adenosine receptors is necessary for the full spectrum of biochemical changes elicited by chronic ingestion of xanthines, such as caffeine, theophylline, and paraxanthine.     

Chemical puzzles in the search for new,flexible derivatives of lurasidone as antipsychotic drugs

In the pharmacotherapy of schizophrenia, there is a lack of effective drugs, and currently used agents cause a large number of side effects. The D₂, 5-HT_1A, 5-HT_2A receptors are among the most important receptor targets in the treatment of schizophrenia, but antagonism at 5-HT₆ and 5-HT₇ receptors may bring about additional improvement of cognitive functions. However, doubt exists regarding the importance of 5-HT₇R in the pharmacotherapy. In 2010, lurasidone (with high affinity for D₂, D₃, 5-HT_1A, 5-HT_2A, 5-HT₇ receptors) was approved for the treatment of schizophrenia. Due to the efficacy of the mentioned drug and doubts related to the role of 5-HT₇R, we decided to obtain compounds with an activity profile similar to that of lurasidone, but with the reduced affinity for 5-HT₇R and increased affinity for 5-HT₆R. For this purpose, we chose a flexible hexyl derivative of lurasidone (2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 1a) as a hit structure. After molecular modeling, we modified it, in the area of the arylpiperazine and imide group, using the moieties found in other known CNS drugs. We received the compounds in accordance with the previously developed method of ecological synthesis in the microwave radiation field. Among the obtained compounds, N-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)naphthalene-sulfonamides 1v and 1w were distinguished as multifunctional ligands showing increased affinity for 5-HT₆R, and 2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 1i – a multifunctional ligand showing moderate affinity for 5-HT₆R and threefold lower for 5-HT₇R. In the paper, we discuss some of the observed dependencies regarding 5-HT₆/5-HT₇R affinity using molecular docking methods.     

Sigma receptors [σRs]: biology in normal and diseased states

This review compares the biological and physiological function of Sigma receptors [σRs] and their potential therapeutic roles. Sigma receptors are widespread in the central nervous system and across multiple peripheral tissues. σRs consist of sigma receptor one (σ₁R) and sigma receptor two (σ₂R) and are expressed in numerous regions of the brain. The sigma receptor was originally proposed as a subtype of opioid receptors and was suggested to contribute to the delusions and psychoses induced by benzomorphans such as SKF-10047 and pentazocine. Later studies confirmed that σRs are non-opioid receptors (not an µ opioid receptor) and play a more diverse role in intracellular signaling, apoptosis and metabolic regulation. σ₁Rs are intracellular receptors acting as chaperone proteins that modulate Ca²⁺ signaling through the IP₃ receptor. They dynamically translocate inside cells, hence are transmembrane proteins. The σ₁R receptor, at the mitochondrial-associated endoplasmic reticulum membrane, is responsible for mitochondrial metabolic regulation and promotes mitochondrial energy depletion and apoptosis. Studies have demonstrated that they play a role as a modulator of ion channels (K⁺ channels; N-methyl-d-aspartate receptors [NMDAR]; inositol 1,3,5 triphosphate receptors) and regulate lipid transport and metabolism, neuritogenesis, cellular differentiation and myelination in the brain. σ₁R modulation of Ca²⁺ release, modulation of cardiac myocyte contractility and may have links to G-proteins. It has been proposed that σ₁Rs are intracellular signal transduction amplifiers. This review of the literature examines the mechanism of action of the σRs, their interaction with neurotransmitters, pharmacology, location and adverse effects mediated through them.